This application is a 371 of PCT/FR99/00727, filed Mar. 29, 1999.
The invention relates, as novel and useful industrial products, to heteroethynylenic compounds. It also relates to the use of these novel compounds in pharmaceutical compositions intended for a use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell differentiation and proliferation, and find applications more particularly in the topical and systemic treatment of dermatological complaints associated with a keratinization disorder, dermatological (or other) complaints with an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether they are benign or malignant. These compounds can also be used in the treatment of degenerative diseases of connective tissue, to combat ageing of the skin, whether this is light-induced or chronological ageing, and to treat cicatrization disorders. They moreover find an application in the ophthalmological field, in particular in the treatment of corneopathies.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
The compounds according to the invention can be represented by the general formula (I) below: 
in which:
xe2x80x83R5 and R6 having the meanings given below,
X represents: O, Se, S(O)n, n being 0, 1 or 2,
Y represents a divalent radical which has the formula: 
xe2x80x83R7, R8, R9 and R10 having the meanings given below,
R2 and R3, taken together, form, with the adjacent aromatic ring, a 5- or 6-membered ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulphur atom,
given that R2 and R3 independently, which may be identical or different, can represent:
a) a hydrogen atom,
b) a radical chosen from the following radicals
methyl,
tert-butyl,
1-methylcyclohexyl,
1-adamantyl,
c) a radical xe2x80x94OR11 
d) a polyether radical
e) a halogen atom
xe2x80x83R11 having the meaning given below,
it being understood that at least one of the substituents R2 and R3 represents (b),
R4 represents a hydrogen atom, a lower alkyl radical, a radical OR12, a polyether radical, a radical COR13 or a halogen atom,
xe2x80x83R12 and R13 having the meanings given below,
Rxe2x80x24 represents a hydrogen atom or a halogen atom,
R5 represents a hydrogen atom or a lower alkyl radical,
R6 represents:
(i) a hydrogen atom
(ii) a lower alkyl radical
(iii) a radical OR14 
R14 having the meaning given below
(iv) a radical of formula 
xe2x80x83Rxe2x80x2 and Rxe2x80x3 having the meanings given below,
R7, R8, R9 and R10, which may be identical or different, represent a hydrogen atom, a lower alkyl radical or an aryl radical,
R11 and R12, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, an optionally substituted aryl radical, an optionally substituted aralkyl radical, a monohydroxyalkyl or polyhydroxyalkyl radical or a lower acyl radical,
R13 represents a lower alkyl radical, a radical OR15 or a radical 
xe2x80x83R15, Rxe2x80x2 and Rxe2x80x3 having the meanings given below,
R14 and R15, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, an aryl radical, an optionally substituted aralkyl radical, a monohydroxyalkyl radical or a polyhydroxyalkyl radical,
Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid residue, or alternatively, taken together with the nitrogen atom, form a heterocycle.
The invention is also directed towards the salts of the compounds of formula (I) when R1 represents a carboxylic acid function and the geometrical and optical isomers of the said compounds of formula (I).
When the compounds according to the invention are in the form of salts, they are preferably salts of an alkali metal or alkaline earth metal, or alternatively of zinc or of an organic amine.
The term xe2x80x9clower alkyl radicalxe2x80x9d means a radical containing from 1 to 6 carbon atoms, and preferably methyl, ethyl, isopropyl, butyl and tert-butyl radicals.
The term xe2x80x9cmonohydroxyalkyl radicalxe2x80x9d should be understood as meaning a radical containing from 1 to 6 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
The term xe2x80x9cpolyhydroxyalkyl radicalxe2x80x9d should be understood as meaning a radical containing from 2 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals or a pentaerythritol residue.
The term xe2x80x9coptionally substituted aryl radicalxe2x80x9d should be understood as meaning a phenyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
The term xe2x80x9coptionally substituted aralkyl radicalxe2x80x9d should be understood as meaning a benzyl or phenethyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
The term xe2x80x9clower acyl radicalxe2x80x9d should be understood as meaning a radical containing from 1 to 4 carbon atoms, in particular an acetyl or propionyl radical.
The term xe2x80x9camino acid residuexe2x80x9d should be understood as meaning a residue derived, for example, from one of the 20 amino acids of L or D configuration which constitute mammalian proteins.
The term xe2x80x9cheterocyclexe2x80x9d preferably means a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in position 4 with a C1-C6 alkyl or mono- or polyhydroxyalkyl radical as defined above.
The term xe2x80x9cpolyether radicalxe2x80x9d means a radical containing from 1 to 6 carbon atoms and from 1 to 3 oxygen or sulphur atoms, such as methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether radicals.
The term xe2x80x9chalogen atomxe2x80x9d preferably means a fluorine, bromine or chlorine atom.
Among the compounds of formula (I) above which fall within the context of the present invention, mention may be made in particular of the following:
Ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate
3-Methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate
3-Methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate
3-Methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate
3-Methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate
3-Methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate
3-Methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
Ethyl 5-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate
5-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid
Ethyl 5-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate
5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid
5-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid
Methyl 5-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoate
3-Propyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetra-hydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
5-(4-Benzyloxy-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid
5-(4-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid
Ethyl 5-[5-adamantan-1-yl-4-(2-methoxyethoxy-methoxy)-2-methylphenylselenyl]-3-methylpent-2-en-4-ynoate
5-[5-Adamantan-1-yl-4-(2-methoxyethoxymethoxy)-2-methylphenylselenyl]-3-methylpent-2-en-4-ynoic acid
5-[5-Adamantan-1-yl-4-(2-methoxyethoxymethoxy)-2-methylphenylselenyl]-3-propylpent-2-en-4-ynoic acid
5-[5-Adamantan-1-yl-4-(2-methoxyethoxymethoxy)-2-methylphenylselenyl]-3-phenylpent-2-en-4-ynoic acid
Ethyl 5-(3,5-di-tert-butyl-2-methoxymethoxy-phenylselenyl)-3-methylpent-2-en-4-ynoate 5-(3,5-Di-tert-butyl-2-methoxymethoxyphenyl-selenyl)-3-methylpent-2-en-4-ynoic acid
Ethyl 3-methyl-5-(5,5,8,8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate
3-Methyl-5-(5,5,8,8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid
5-[4-Adamantan-1-yl-3-(2-methoxyethoxymethoxy)-phenylselenyl]-3-propylpent-2-en-4-ynoic acid
Ethyl 5-[2-(adamantan-1-yl)-1-methoxyethoxymethoxyphen-5-ylselenyl)-3-methylpent-2-en-4-ynoate
Ethyl 5-[4-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl]-3-methylpent-2-en-4-ynoate
(Z)-5-[4-(2-Methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl]-3-methylpent-2-en-4-ynoic acid
(E)-5-[4-(2-Methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl]-3-methylpent-2-en-4-ynoic acid
Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)penta-2,4-diynoate
Ethyl 5-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate
5-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid
Ethyl 5-[3-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoate
5-[3-(2-Methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoic acid
Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)penta-2,4-diynoate
Ethyl 5-(4-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate
Ethyl 5-[3-[5-(tert-butyldimethylsilanyloxy)-pentyloxymethyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoate
5-[3-[5-(tert-Butyldimethylsilanyloxy)pentyl-oxymethyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoic acid
Ethyl 5-[3-(5-hydroxypentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoate
5-(4-Fluoro-3-methylphenylselenyl)-3-methlpent-2-en-4-ynoic acid
3-Methyl-5-p-tolylselenylpent-2-en-4-ynoic acid
5-(6-Bromo-4,4-dimethylthiochroman-8-ylselenyl)-3-methylpent-2-en-4-ynoic acid.
According to the present invention, the compounds of formula (I) which are more particularly preferred are those for which at least one, and preferably all, of the following conditions is (are) satisfied:
R1 represents a radical xe2x80x94COR6;
X represents an Se or S radical;
the group xe2x80x94Xxe2x80x94Yxe2x80x94R1 is in the para position relative to the substituent R3 on the aromatic ring;
R2 and R3, taken together, form, with the adjacent aromatic ring, a 5- or 6-membered ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulphur atom, or R2 or R3 is a 1-adamantyl radical.
A subject of the present invention is also processes for preparing the compounds of formula (I), in particular according to the reaction schemes given in FIGS. 1 and 2.
With reference to FIG. 1, the derivatives of formula (Ia) can be prepared by a sequence of reactions comprising the action of a base such as potassium hydride or sodium hydride on the product (1), followed by coupling with trichloroethylene. The product (2) obtained is subjected to the action of a lithiated base such as BuLi in a solvent such as THF. The acetylene derivative (3) obtained can be coupled with a disubstituted alkyne in the presence of a palladium catalyst.
With reference to FIG. 2, the derivatives of formula (Ib) can be prepared by a sequence of reactions comprising the action of a lithiated base such as tBuLi on the product (4) in a solvent such as THF, followed by the addition of selenium and the formation of the dimer by oxidation in basic medium (EtOH, NAOH). The product (5) obtained is subjected to the action of bromine in a solvent such as THF and is then coupled with a true acetylene derivative in the presence of a copper catalyst.
The product (Ia) with Y other than an oxygen atom can be oxidized to sulphone or sulphoxide by the action of an oxidizing agent such as meta-perbenzoic acid or sodium periodate.
When R1 represents a COOH radical, the compounds are prepared by protecting R1 with a protecting group of alkyl type. Saponification of the ester function in the presence of a base such as sodium hydroxide or lithium hydroxide in an alcoholic solvent or in THF gives the corresponding acids.
When R1 represents an alcohol radical, the compounds can be obtained from the acid by reduction in the presence of hydride such as boron hydride. The alcohol can be etherified according to the standard methods.
When R1 represents an aldehyde radical, the compounds can be obtained by oxidation of the corresponding alcohols by the action of manganese oxide or pyridinium dichromate.
When R1 represents an amide radical, the compounds can be obtained by conversion of the acid to the acid chloride, followed by reaction with a suitable amine.
These compounds bind to the RXR receptors, some having agonist activity, others having antagonist activity. Some of these compounds can also bind to the RAR receptors.
The binding and transactivation properties as RXR-receptor agonists can be determined by methods known in the art, such as, for example: Levin et al., Nature 1992, 355, 359-61; Allenby et al., Proc. Natl. Acad. Sci., 1993, 90, 30-4.
The RXR-agonist activity can also be determined by the test described in French patent application No. 95/07301 filed on Jun. 19, 1995 by the Applicant. This test comprises the following steps: (i) a sufficient amount of a compound which is an active ligand for at least one receptor of the superfamily of steroidal/thyroid nuclear receptors other than a ligand specific for the RXR receptors and which can heterodimerize with the RXRs, such as an RAR-agonist molecule, is applied topically to a part of the skin of a mammal, (ii) a molecule capable of having RXR-agonist activity is administered systemically or topically to this same part of the skin of the mammal before, during or after step (i), and (iii) the response on the part of the mammal""s skin thus treated is evaluated. Thus, the response to a topical application to a mammal""s ear of an RAR-agonist molecule which corresponds to an increase in the thickness of this ear can be increased by the systemic or topical administration of an RXR-receptor agonist molecule.
The RXRa-antagonist activity can be evaluated in the transactivation test by determination of the dose (IC50) which gives 50% inhibition of the transactivating activity of an RXRa-selective agonist: 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]nicotinic acid (CD 3127) according to the following procedure:
HeLa cells are co-transfected with an expression vector coding for RXRa (p565-RXRa) and a reporter plasmid containing the response element 1/2 CRBP II cloned upstream of the thymidine kinase heterologous promoter and of the chloramphenicolmacetyl-transferase (CAT) reporter gene. Eighteen hours after co-transfection, the cells are treated with a fixed concentration of CD 3127 and increasing concentrations of the molecule to be evaluated. After treatment for twenty-four hours, the CAT activity is assayed by ELISA. The fixed concentration of CD3127 used is 10xe2x88x928M and corresponds to its EC50.
A subject of the present invention is thus, as a medicinal product, the compounds of formula (I) as defined above.
The compounds according to the invention are particularly suitable in the following fields of treatment:
1) for treating dermatological complaints associated with a keratinization disorder which has a bearing on differentiation and on proliferation, in particular for treating common acne, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, medication-related or occupational acne,
2) for treating other types of keratinization disorder, in particular ichthyosis, ichthyosiform states, Darier""s disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, and cutaneous or mucous (buccal) lichen,
3) for treating other dermatological complaints associated with a keratinization disorder with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether it is cutaneous, mucous or ungual psoriasis, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory complaints which have no keratinization disorder,
4) for treating all dermal or epidermal proliferations, whether benign or malignant and whether they are of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, it being also possible for the oral or florid papillomatoses and the proliferations to be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma,
5) for treating other dermatological disorders such as bullosis and collagen diseases,
6) for treating certain ophthalmological disorders, in particular corneopathies,
7) for repairing or combating ageing of the skin, whether this is light-induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic ageing,
8) for preventing or curing the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) for preventing or treating cicatrization disorders or for preventing or repairing stretch marks, or alternatively for promoting cicatrization,
10) for combating disorders of sebaceous functioning such as the hyperseborrhoea of acne or simple seborrhoea,
11) in the treatment or prevention of cancerous or precancerous states,
12) in the treatment of inflammatory complaints such as arthritis,
13) in the treatment of any general or skin complaint of viral origin,
14) in the prevention or treatment of alopecia,
15) in the treatment of dermatological or general complaints having an immunological component,
16) in the treatment of complaints of the cardiovascular system such as arteriosclerosis, hypertension, non-insulin-dependent diabetes and obesity,
17) in the treatment of skin disorders due to an exposure to UV radiation.
In the therapeutic fields mentioned above, the compounds according to the invention may be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, a-hydroxy or a-keto acids or derivatives thereof, or alternatively ion-channel blockers. The expression xe2x80x9cD vitamins or derivatives thereofxe2x80x9d means, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3. The expression xe2x80x9canti-free-radical agentsxe2x80x9d means, for example, a-tocopherol, superoxide dismutase, ubiquinol or certain metal-chelating agents. The expression xe2x80x9ca-hydroxy or a-keto acids or derivatives thereofxe2x80x9d means, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acid or the salts, amides or esters thereof. Lastly, the term xe2x80x9cion-channel blockersxe2x80x9d means, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.
A subject of the present invention is also medicinal compositions containing at least one compound of formula (I) as defined above, one of the optical or geometrical isomers thereof or one of the salts thereof.
A subject of the present invention is thus a novel medicinal composition intended in particular for treating the abovementioned complaints, and which is characterized in that it comprises, in a pharmaceutically acceptable support which is compatible with the mode of administration selected for this composition, at least one compound of formula (I), one of the optical or geometrical isomers thereof or one of the salts thereof.
The compounds according to the invention may be administered enterally, parenterally, topically or ocularly.
Via the enteral route, the medicinal products may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or polymeric or lipid vesicles which enable controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight taken in 1 to 3 doses.
Via the topical route, the pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and the mucosae and may be in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or polymeric or lipid vesicles or polymeric patches and hydrogels which enable controlled release. These topical-route compositions may either be in anhydrous form or in aqueous form, depending on the clinical indication.
Via the ocular route, they are mainly eyedrops.
These compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of the optical or geometrical isomers thereof or alternatively one of the salts thereof, at a concentration preferably of between 0.001% and 5% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene and especially for treating skin types with a tendency towards acne, for promoting the regrowth of the hair, for combating hair loss, for combating the greasy appearance of the skin or the hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin types, and for preventing and/or combating light-induced or chronological ageing.
In the cosmetic field, the compounds according to the invention can moreover be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, a-hydroxy or a-keto acids or derivatives thereof, or alternatively with ion-channel blockers, all of these various products being as defined above.
The present invention is thus also directed towards a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable support which is suitable for topical application, at least one compound of formula (I) as defined above or one of the optical or geometrical isomers thereof or one of the salts thereof, it being possible for this cosmetic composition to be, in particular, in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or polymeric or lipid vesicles, a soap or a shampoo.
The concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight relative to the entire composition.
The medicinal and cosmetic compositions according to the invention can also contain inert additives or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and derivatives thereof, or urea; anti-seborrhoea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, the salts and the derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular, b-carotene; anti-psoriatic agents such as anthraline and derivatives thereof, and, lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, the esters and the amides thereof.
The compositions according to the invention may also contain flavour-enhancing agents, preserving agents such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as a-tocopherol, butylhydroxyanisole or butylhydroxytoluene.